Research progress on individualized administration of linezolid based on population pharmacokinetics / 中国药房

Linezolid is an antibacterial agent for the treatment of multi-resistant Gram-positive bacterial infections， which is widely used in clinical practice. However， there are large individual differences in the pharmacokinetic characteristics of the drug in patients， and it is difficult to obtain the optimal therapeutic effect when the drug is administered according to the conventional dose in the instructions. Therefore， it is necessary to carry out therapeutic drug monitoring （TDM） for linezolid， and guide and optimize its antibacterial treatment plan by using population pharmacokinetics （PPK） and pharmacodynamics principles. This paper summarizes the PPK changes and the research progress of individualized administration of linezolid in various populations， and recommends that the patient’s steady-state blood concentration is kept at 2-8 mg/mL through TDM when using linezolid clinically. It is recommended to appropriately reduce the dosage for patients with liver and kidney dysfunction， appropriately increase the dosage for obese， burned and children patients， and provide pharmaceutical monitoring during the medication process to promote rational drug use.

Risk factors of linezolid-related thrombocytopenia in patients in the department of hepatobiliary surgery / 药学实践杂志

Objective To provide the evidence for clinical medication safety by the investigation of the risk factors of linezolid-related thrombocytopenia in cancer patients in the department of hepatobiliary surgery. Methods Patients who received linezolid for anti-infective treatment from January 2017 to December 2021 were selected. The patients were divided into thrombocytopenia group and non-thrombocytopenia group according to whether thrombocytopenia occurred or not after administration of linezolid. The general data and laboratory indicators of the two groups were compared, and the risk factors of linezolid-related thrombocytopenia were screened by multivariate logistic regression analysis. Results A total of 104 patients were included in the study, including 84 patients who underwent surgery and 20 patients who did not. The incidence of linezolid-related thrombocytopenia was 24.0%. There were significant differences in gender, age, duration of linezolid use, platelet count, white blood cell count, alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin, creatinine, estimated glomerular filtration rate between the two groups (P<0.05); logistic regression analysis suggested that age ≥60 years (OR=7.093; P=0.017), duration of linezolid use ≥12 days (OR=4.399; P=0.035), baseline platelet count ≤200×109/L (OR=8.470; P=0.004), baseline AST≥50 U/L (OR=15.465; P<0.001), and baseline white blood cell count ≥11×109/L (OR=11.436; P=0.001) were the risk factors for linezolid-related thrombocytopenia in cancer patients. Conclusion During the treatment of linezolid in cancer patients, attention should be paid to the adverse reactions of thrombocytopenia in the patients, especially those with old age, long-term treatment, low baseline platelets, poor baseline liver function, and high baseline white blood cell counts.

Validation of a fast and reliable liquid chromatography tandem mass spectrometry for simultaneous quantitation of Voriconazole, Posaconazole and Linezolid in human serum / 中华检验医学杂志

Objective:To establish a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of voliconazole (VRC), posaconazole (PCZ), and linazolam (LNZ) in human serum.Methods:This study is a methodological validation by LC-MS/MS. The blood concentration results of VRC, PCZ, and LNZ in our hospital′s anti-infection patients were collected. Voriconazole, Posaconazole, and Linezolid were accurately weighed and prepared. Linezolid-[2H3] was used as the internal standard. After gradient elution on the ACE PFP column, the residuals were analyzed by LC-MS/MS in the positive electrospray ionization mode and multiple reaction monitor (MRM) mode. The method′s linearity, precision, lower limit of detection, and recovery rate were validated according to standard guidelines.Results:The linear correlation coefficient ( r) of the standard curve was above 0.99 ( r>0.99). The linear range of VRC and PCZ were 0.10 mg/L~10.00 mg/L, and the lower limit of detection were 0.01 mg/L. The linear range of LNZ was 0.50 mg/L~50.00 mg/L, and the lower limit of detection was 0.05 mg/L. The recoveries of VRC, PCZ and LNZ were 90.96%-103.18%, 91.84%-99.17%, and 97.04%-100.41%, respectively. Intra-and inter-batch precision (% CV) for VRC were less than 8.30%. Intra-and inter-batch precision (% CV) for PCZ was less than 9.78%. Intra-and inter-batch precision (% CV) for LNZ was less than 7.14%. Drug concentrations in 155 cases of VRC, 44 cases of PCZ, and 59 cases of LNZ were detected. Conclusion:We have established an LC-MS/MS method for the rapid, accurate, highly specific determination of VRC, PCZ, and LNZ concentrations in human serum. This method is suitable for analyzing large clinical sample sets.

Comparison of omadacycline and meropenem plus linezolid in treatment of pulmonary infection: A real-world cohort study / 中华临床感染病杂志

Objective:To compare the efficacy and safety of omacycline with meropenem plus linezolid in the treatment of patients with pulmonary infection.Methods:The clinical data of 58 patients with pulmonary infection admitted to the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou Red Cross Hospital and Jiande First People’s Hospital from December 2021 to May 2022 were retrospectively analyzed. The patients were divided into the omacycline group ( n=29) and the meropenem combined with linezolid group (combined group, n=29). The omacycline group was given intravenous omacycline 200 mg or 100 mg, q. d, and the combined group was given intravenous meropenem (1 000 mg, t.i.d) and linezolid (600 mg, b. i.d). The clinical efficacy and drug-related adverse events of two groups were observed. SPSS 22.0 statistical software was used for data analysis. Results:In the omacycline group, 8 cases (27.6%, 8/29) were cured, 19 cases (65.5%, 19/29) were improved, and 2 cases (6.9%, 2/29) were worsened. In the combined group, 1 case (3.4%, 1/29) was cured, 26 cases (89.7%, 26/29) were improved, and 2 cases (6.9%, 2/29) died. There was a statistically significant difference between the two groups ( χ2=6.533, P=0.038). The respiratory failure occurred in 3 cases (10.3%, 3/29) of the omacycline group and 5 cases (17.2%, 5/29) of the combined group ( χ2=0.580, P=0.446). In those patients who were cured or improved, the median time from treatment initiation to disease remission was 3.0 (2.0, 5.5) d in the omacycline group and 5.0 (4.0, 6.0) d in the combined group ( Z=-2.122, P=0.034). There was no significant difference in the incidence of adverse reactions between the two groups [6.9% (2/29) vs. 13.8% (4/29), χ2=0.744, P=0.389]. Conclusion:Omacycline exhibits a good efficacy and safety in the treatment of patients with pulmonary infection, which may be prioritized for the treatment of pulmonary infections.

Avances en tuberculosis en el 54° congreso chileno de enfermedades respiratorias. 1ra parte: nuevos esquemas acortados para tuberculosis drogoresistente ¿son adecuados para todos? / New shortened schemes for drug-resistant tuberculosis: are they suitable for everyone?

En esta presentación se realiza un recorrido a través de los diferentes esquemas terapéuticos de la tuberculosis drogo-resistente. Se muestra como los investigadores utilizan los nuevos fármacos disponibles y desarrollan diferentes esquemas cada vez más acortados y de administración por vía oral exclusiva, con la intención de lograr una mayor eficacia de curación de la tuberculosis resistente, con menos efectos colaterales y menor letalidad. La búsqueda de esquemas con una duración similar a las terapias de casos sensibles de tuberculosis (esquemas primarios de 6 meses) es el objetivo principal. Las pruebas moleculares como el Xpert ayudan enormemente a seleccionar los esquemas de terapia, según el perfil de susceptibilidad de los casos (resistencia a isoniazida, rifampicina, fluorquinolonas y combinaciones). Las terapias actuales de la tuberculosis drogo-resistente se basan en nuevos fármacos como fluorquinolonas, bedaquilina y linezolid, pero otros fármacos como pretomanid y delamanid también están siendo recomendados.

This presentation takes a tour through the different therapeutic schemes of drug-resistant tuberculosis. It shows how researchers use the new drugs available and develop different increasingly shortened schedules and exclusive oral administration, with the intention of achieving greater efficacy in curing resistant tuberculosis, with fewer side effects and lower lethality. The search for regimens with a duration similar to therapies of sensitive cases of tuberculosis (primary regimens of 6 months) is the main objective. Molecular tests, such as Xpert, greatly help in selecting therapy regimens, according to the susceptibility profile of the cases (resistance to isoniazid, rifampicin, fluorquinolones and combinations). Current drug-resistant tuberculosis therapies are based on new drugs such as fluorquinolones, bedaquiline and linezolid, but other drugs such as pretomanid and delamanid are also being recommended.

Risk of acute kidney injury and cost-effectiveness analysis comparing vancomycin and linezolid for the treatment of pediatric patients infected with Gram-positive bacteria / Risco de lesão renal aguda e custo-efetividade comparando vancomicina e linezolida para o tratamento de pacientes pediátricos infectados por bactérias Gram-positivas

Objective: This study aimed to compare the occurrence of acute kidney injury (AKI) in pediatric patients who used vancomycin (VAN) or linezolid (LNZ) to treat Gram-positive coccus (GPC) infections and to assess which treatment (VAN or LNZ) is the most cost-effective considering a pediatric hospital perspective. Methods: A retrospective cohort was performed to evaluate the occurrence of nephrotoxicity in pediatric patients without previous AKI, with GPC infections that used LNZ, or VAN monitored by serum VAN levels. Initially, descriptive analysis and Fisher and chisquare test were performed for this comparison. Then, a cost-effectiveness analysis was conducted through a decision tree model. The outcomes of interest were the rate of AKI related to the drug and the rate of admission to the intensive care unit (ICU) and cure. Results: In patients without previous acute kidney injury (AKI), 20% developed nephrotoxicity associated with VAN versus 9.6% in the LNZ group (p = 0.241). As there was no difference in nephrotoxicity between VAN andlinezolid (LNZ), vancomycin (VAN) monitored by serum VAN levels can optimize and rationalize the treatment. The nephrotoxicity risk criterion should not guide the prescription for LNZ. Furthermore, the average global cost of treatment with VAN was approximately R$ 43,000, while for LNZ, it was R$ 71,000. Conclusion: VAN was considered dominant (lower cost and greater effectiveness) over LNZ for treating patients with GPC infection.

Objetivo: Este estudo objetivou comparar a ocorrência de lesão renal aguda (LRA) em pacientes pediátricos que usaram vancomicina (VAN) ou linezolida (LNZ) para tratar infecções por cocos Gram-positivos (CGP) e avaliar qual tratamento (VAN ou LNZ) é o mais custo-efetivo considerando a perspectiva de um hospital pediátrico. Métodos: Foi realizada uma coorte retrospectiva para avaliar a ocorrência de nefrotoxicidade em pacientes pediátricos sem LRA prévia, com infecções por CGP que utilizaram LNZ ou VAN, combinada com vancocinemia. Para essa comparação, inicialmente foram realizados análise descritiva e testes de Fisher e qui-quadrado. Em seguida, foi realizada uma análise de custo-efetividade por meio de um modelo de árvore de decisão. Os desfechos de interesse foram a taxa de LRA relacionada ao medicamento e a taxa de internação em unidade de terapia intensiva e cura. Resultados: Nos pacientes sem LRA prévia, 20% deles desenvolveram nefrotoxicidade associada à VAN versus 9,6% no grupo LNZ (p = 0,241). Como não houve diferença na nefrotoxicidade entre VAN e LNZ, a VAN combinada com a vancocinemia pode otimizar e racionalizar o tratamento, e a prescrição de LNZ não deve ser guiada pelo critério de risco de nefrotoxicidade. Além disso, o custo médio global do tratamento com VAN foi de aproximadamente R$ 43.000, enquanto para LNZ foi de R$ 71.000. Conclusão: Assim, a VAN foi considerada dominante (menor custo e maior eficácia) sobre a LNZ para o tratamento de pacientes com infecção por CGP.

Transição de via de linezolida endovenosa para via oral: uma análise de custo-minimização / Switching from intravenous to oral linezolid therapy: a cost-minimization analysis

Objetivo: Comparar custos da terapia endovenosa exclusiva com linezolida com os custos da terapia iniciada por via endovenosa com transição para via oral após 72 horas, como estratégia de intervenção em programas de gestão de antimicrobianos. Métodos: Avaliação econômica de custo-minimização comparando custos diretos da terapia endovenosa exclusiva com linezolida com a terapia endovenosa seguida de transição para via oral em cenário simulado, sob a perspectiva do Sistema Único de Saúde (SUS), com árvore de decisão como modelo para tomada de decisão. Resultados: A alternativa englobando a transição de via mostrou-se a mais econômica em todos os cenários analisados. Para 28 dias de tratamento com linezolida, houve redução de 22% nos custos, considerando o paciente internado. Ao considerar alta após o sexto dia de tratamento, a redução de custos variou de 26%, com financiamento pelo SUS do restante do tratamento, a 84%, com financiamento do tratamento pós-alta pelo paciente. Conclusão: Conclui-se que a transição de via de linezolida é uma importante estratégia nos programas de gerenciamento de antimicrobianos, capaz de gerar economia significativa para a instituição. As avaliações econômicas de custo-minimização, nesse contexto, são uma importante ferramenta para demonstrar o aspecto econômico com potencial para sensibilizar gestores e tomadores de decisão.

Objective: To compare the direct costs of linezolid intravenous therapy with the costs of intravenous therapy switching to oral therapy after 72 hours as an intervention strategy in antimicrobial stewardship programs. Methods: Economic evaluation cost-minimization comparing direct costs of exclusive linezolid intravenous therapy with intravenous therapy for 72 hours and after switching to oral therapy in a simulated scenario, from the perspective of the National Health Service, with a decision tree as a decision modeling. Results: The alternative encompassing the therapy transition proved to be the most economical in all analyzed scenarios. For 28 days of treatment with linezolid, there was a 22% reduction in costs, considering the hospitalized patient. When considering discharge after the sixth day of treatment, the cost reduction ranged from 26%, with funding from the National Health Service for the rest of the treatment, to 84%, with funding for the post-discharge treatment by the patient. Conclusion: It was concluded that the linezolid therapy transition is an important strategy in antimicrobial management programs, capable of generating significant savings for the institution. In this context, economic cost-minimization assessments are an important tool to demonstrate the economic aspect with the potential to raise awareness among managers and decision-makers.

Genotypic characterization of vancomycin-resistant Enterococcus causing urinary tract infection in northern India

Background & objectives: Infections caused by vancomycin-resistant Enterococci are difficult to treat given the limited therapeutic alternatives. Different gene clusters are known to confer vancomycin resistance. vanA and vanB genes are transferable and are clinically relevant. This cross-sectional study aimed to identify the vancomycin-resistant genotypes in the strains causing urinary tract infection and also to test the in vitro efficacy of linezolid and pristinamycin against the vancomycin-resistant isolates. Methods: Antimicrobial resistance profile of 118 enterococcal isolates was evaluated. Minimum inhibitory concentration of vancomycin, teicoplanin and high-level gentamicin (HLG) was determined by micro broth dilution. The vancomycin-resistant isolates were tested against linezolid and pristinamycin by micro-broth dilution and E strip method. The presence of vancomycin-resistant genes was detected by multiplex polymerase chain reaction and was sequenced and analyzed. Results: Most commonly isolated species were Enterococcus faecalis (76.9%) and Enterococcus faecium (16.9%). It was found that 43 per cent of the isolates were resistant to HLG and 16.9 per cent to vancomycin. Higher resistance was seen against fluoroquinolones, erythromycin, tetracycline and ?-lactam drugs. However, 5.08 per cent strains were resistant to tigecycline. All vancomycin-resistant strains were sensitive to pristinamycin and one was resistant to linezolid. vanA and vanB gene were found in 15 and five isolates, respectively. The gene sequences were submitted to NCBI gene bank and accession numbers were obtained. Interpretation & conclusions: The present study showed prevalence of vanA and vanB genes carrying Enterococcus in a tertiary care centre in north India. The emergence of resistance against drugs such as tigecycline and linezolid is a topic of concern as it will be a therapeutic challenge for physicians.

Adverse reactions of linezolid in the treatment of multidrug-resistant pulmonary tuberculosis / 中华传染病杂志

Objective:To analyze the adverse reactions of patients with multidrug-resistant pulmonary tuberculosis treated with linezolid, and to provide reference for clinical rational use of drugs.Methods:A total of 189 patients with multidrug-resistant pulmonary tuberculosis who were admitted to Hunan Chest Hospital between June 2019 and June 2020 were retrospectively included, and were divided into the linezolid group and the control group. The control group was given a standardized anti-tuberculosis treatment without linezolid, and the linezolid group was given linezolid in addition to standardized regimens. The occurrences of hematological toxicity, peripheral neuritis, optic neuritis and other adverse reactions in the two groups after anti-tuberculosis treatment were recorded. The risk factors for adverse reactions of linezolid were analyzed. Statistical analysis was performed using independent samples t test and chi-square test, and logistic regression was used to analyze the risk factors for adverse reactions of linezolid. Results:A total of 189 patients with MDR-TB were included in this study, including 108 in the linezolid group and 81 in the control group. There were no significant differences in baseline characteristics between the linezolid and control groups. The frequencies of leukopenia, anemia, thrombocytopenia, peripheral neuritis and optic neuritis in the linezolid group were 20.4%(22/108), 47.2%(51/108), 21.3%(23/108), 20.4%(22/108) and 13.9%(15/108), respectively, which were all significantly higher than those in the control group (8.6%(7/81), 27.2%(22/81), 9.9%(8/81), 1.2%(1/81) and 4.9%(4/81), respectively), and the differences were all statistically significant ( χ2=4.90, 7.86, 4.40, 15.86 and 4.10, respectively, all P<0.050). Patients older than 45 years of age was independent risk factor for leukopenia (odds ratio ( OR)=3.08, 95% confidence interval ( CI) 1.03 to 9.25, P<0.050) and thrombocytopenia ( OR=2.41, 95% CI 1.09 to 5.35, P<0.050) after linezolid administration. The higher value of white blood cell at baseline ( OR=0.48, 95% CI 0.30 to 0.76, P=0.002) was an independent protective factor for leukopenia associated with linezolid. Conclusions:Pancytopenia, peripheral neuritis and optic neuritis are prone to appear when linezolid is used to treat patients with multidrug-resistant pulmonary tuberculosis. In clinical practice, closely monitoring the adverse reactions during the use of linezolid for anti-tuberculosis treatment is needed.

Lactic acidosis associated with standard dose linezolid in a kidney recipient with impaired renal function

Abstract Severe lactic acidosis, a mitochondrial toxicity caused by the recommended standard dosage of linezolid (LZD), may occur in patients with impaired renal function. We describe an adult male who underwent kidney transplantation with stably impaired renal function, severe dyspnea, and abdominal discomfort. He received a standard oral dose of LZD (600 mg twice daily) and azithromycin for three weeks with a reduced immunosuppressant dose due to pulmonary non-tuberculosis mycobacterial infection. He was alert and afebrile, with a blood pressure of 140/60 mmHg. Pertinent laboratory data showed: pH 7.12, PaCO2 13.6 mmHg; HCO3- 4.3 mmol/L and serum lactate 18.4 mmol/L. His trough serum LZD concentration reached toxic levels (21.4 μg/mL). With hemodialysis, his clinical symptoms improved, with a decline in serum LZD (9.8μg/mL) and lactate (3.2 mmol/L). Chronic standard dose LZD in patients with impaired renal function can lead to life-threatening lactic acidosis, especially in coexisting conditions that reduce LZD metabolism.

Vancomycin and Linezolid dosing in Obese and Overweight Patients: Is There a Universally Accepted Dosing Protocol to Improve their Efficacy?

@#Vancomycin is used to manage methicillin-resistant Staphylococcus aureus (MRSA) and other bacterial infections that are Gram-positive in nature. Linezolid belongs to the oxazolidinone class of antibiotics, which is primarily used to treat vancomycin-resistant Enterococcus (VRE), MRSA, diabetic foot, soft tissue, and skin infections. Here, we discuss vancomycin and linezolid dosing in obese patients, their mechanism of actions, pharmacokinetics, problems with dosing and evaluation of several dosing protocols in the obese patient population. There is no generally accepted dosing protocol for linezolid and vancomycin. Evidence suggests that using trough concentrations alone is insufficient for estimating vancomycin and linezolid exposure accurately as many researchers have revised protocol guidelines, developed more rigorous dosing and monitoring guidelines, or developed novel dosage strategies to meet the needs of overweight patients. Peaks and troughs measurement should be considered because it improves precision and reduces the area under the curve (AUC) estimate bias. To provide better dosing guidelines in this vulnerable group, obese patients must be included in all phases of drug design.

Monte Carlo simulation study to optimize administration regimens of linezolid, teicoplanin and daptomycin for Staphylococcal bloodstream infections / 中华传染病杂志

Objective:To predict and evaluate the antibacterial efficacy of linezolid, teicoplanin and daptomycin against Staphylococci bloodstream infections with Monte Carlo simulation, and to optimize the clinical administration program. Methods:A total of 1 847 Staphylococci strains isolated from blood samples between January 2018 to December 2019 were collected with the help of the Blood Bacterial Resistant Investigation Collaborative System (BRICS). Minimum inhibitory concentrations (MIC) of linezolid and daptomycin were detected by broth dilution method, while MIC of teicoplanin were detected by agar dilution method. The dosage regimens of linezolid were 800 mg once daily, 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours. The dosage regimens of teicoplanin were 400 mg once every 12 hours, 600 mg once every 12 hours, 800 mg once every 12 hours, and 1 000 mg once every 12 hours. The dosage regimens of daptomycin were 4 mg·kg -1·d -1, 6 mg·kg -1·d -1, 8 mg·kg -1·d -1, 10 mg·kg -1·d -1and 12 mg·kg -1·d -1. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of three different dosage regimens were calculated by Monte Carlo simulation. A dosage regimen with CFR≥90.0% was a reasonable choice for empirical antimicrobial therapy. Results:PTA of linezolid against Staphylococci when MIC≤0.500 mg/L at four dosage regimens (800 mg once daily, 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours) were all over 90.0%. When MIC was 1.000 mg/L, the PTA of linezolid against Staphylococci under the dosages of 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours were 92.2%, 96.6% and 97.6%, respectively. The CFR of the four dosage regimens of linezolid were 73.9%, 83.7%, 90.8% and 95.3%, respectively. When MIC≤1.000 mg/L, PTA of teicoplanin against Staphylococci were all 100.0% at four dosage regimens (400 mg once every 12 hours, 600 mg once every 12 hours, 800 mg once every 12 hours and 1 000 mg once every 12 hours). When MIC was 2.000 mg/L, the PTA of teicoplanin (800 mg once every 12 hours and 1 000 mg once every 12 hours) against Staphylococci were both 100.0%. The CFR of the four dosage regimens of teicoplanin were 90.8%, 92.8%, 93.5% and 94.6%, respectively. When MIC≤0.500 mg/L, PTA of daptomycin against Staphylococci under the five dosages of 4 mg·kg -1·d -1, 6 mg·kg -1·d -1, 8 mg·kg -1·d -1, 10 mg·kg -1·d -1 and 12 mg·kg -1·d -1 were all over 90.0%. When MIC was 1.000 mg/L, the PTA of daptomycin against Staphylococci under the three dosages of 8 mg·kg -1·d -1, 10 mg·kg -1·d -1 and 12 mg·kg -1·d -1were 96.9%, 100.0% and 100.0%, respectively. The CFR of the five dosage regimens of daptomycin against Staphylococci were 97.4%, 99.2%, 99.9%, 100.0% and 100.0%, respectively. Conclusions:Linezolid (600 mg once every 12 hours), teicoplanin (400 mg once every 12 hours) and daptomycin (4 mg·kg -1·d -1) can achieve satisfactory antibacterial activity for Staphylococci bloodstream infections.

Efficacy of linezolid in the treatment of gram-positive coccal infections after chemotherapy in older adult patients with leukemia / 中国基层医药

Objective:To investigate the clinical efficacy and adverse reactions of linezolid in the treatment of gram-positive coccal infections after chemotherapy in older adult patients with leukemia.Methods:Ninety-two older adult patients with leukemia complicated by gram-positive coccal infections, who received treatment in Yiwu Central Hospital from January 2017 to December 2019, were included in this study. They were randomly assigned to receive routine anti-infection treatment (control group, n = 46) or linezolid treatment (observation group, n = 46). Clinical efficacy, the time required for body temperature restoring to normal, and medication time were compared between the two groups. Results:Total response rate was significantly higher in the observation group than in the control group [95.65% (44 /46) vs. 78.26% (36/46), χ2 = 6.13, P = 0.013]. The time required for body temperature restoring to normal and medication time in the observation group were (7.98 ± 1.04) days and (8.58 ± 1.31) days, respectively, which were significantly shorter than those in the control group [(8.85 ± 1.47) days, (9.46 ± 2.52) days, t = 3.27, 2.10, P = 0.001, 0.019). The incidence of adverse reactions was significantly lower in the observation group than in the control group [4.35% (2/46) vs. 19.57% (9/46), χ2 = 5.05, P < 0.05]. Conclusion:Linezolid is highly effective on gram-positive coccal infections after chemotherapy in older adult patients with leukemia. Linezolid treatment requires comparatively shorter time required for body temperature restoring to normal and shorter medication time and is safer than routine anti-infection treatment.

Determination of azide genotoxic impurity in linezolid API and glucose injection by UPLC-MS/MS / 中国药科大学学报

@#A UPLC-MS/MS method was established for the determination of the genotoxic impurity (R)-5-(azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone in linezolid API and its glucose injection. Chromatographic separation was performed on a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 μm) with 0.1% formic acid water-0.1% formic acid acetonitrile (60∶40) at a flow rate of 0.3 mL/min. The UPLC-MS/MS was equipped with electrospray ionization in positive ionization mode and multiple reaction monitoring mode. The results showed that the calibration curve was linear in the range of 4-12 ng/mL and the limit of quantification was 0.073 ng/mL.The average recoveries of the low, medium and high concentration (80%,100%,120% limit concentration) loading solutions were 101.14%, 100.59% and 101.47%, respectively (RSDs:0.73%, 1.10% and 0.91%, respectively).The sample solution was stable for 6 d.No genotoxic impurity of (R)-5-(Azidomethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinonewas not detected in the samples of linezolid API and its glucose injection.

Progress in individualized use of linezolid in adult critically ill patients / 中国药房

Linezolid is a n anti-infective drug commonly used in clinic. Considering the large difference of individual condition ， severe basic disease ，poor organ function and large variety and quantity of drugs ，standard dose of linezolid may not be suitable for all critically ill patients. This paper reviews the relevant researches on the application of linezolid in adult critically ill patients in recent years ，analyzes the pharmacokinetic characteristics of critically ill patients ，and summarizes the influence of common physiological and pathological changes in critically ill patients on drugs. When using linezolid ，the clinical comprehensive evaluation of this special group should be strengthened. In addition to appropriately reducing the drug dosage of patients with liver/ kidney function injury ，it is also necessary to consider appropriately increasing the drug dosage in other cases. After medication ，in order to avoid excessive or insufficient drug exposure ，clinical medication monitoring should be strengthened ，especially the important mean as therapeutic drug monitoring should be used well.

Linezolid-resistant Enterococcus casseliflavus and Enterococcus gallinarum isolated from poultry farms in Kelantan, Malaysia

Aims@#Linezolid has become a decisive therapy in treating infections with vancomycin-resistant Enterococcus (VRE). Currently, the emergence of linezolid-resistant Enterococcus further complicates the therapeutic options and leads to global health threat not only in hospital setting but in the community. The study aimed at antimicrobial pattern of Enterococcus isolated from 6 poultry farms in Kelantan, Malaysia.@*Methodology and results@#Between February and December 2019, 300 broiler cloacal swab sample (Gallus gallus domesticus) were collected and screened for linezolid-resistant enterococci (LRE) using a standard biochemical and antimicrobial susceptibility tests. Among all the samples, 32.3% (n=97/300) grew Enterococcus, 71.1% (n=69/97) of it were identified Enterococcus casseliflavus by molecular identification, whilst remaining isolates 28.9% (n=28/97) were further identified as Enterococcus gallinarum by 16S rRNA sequencing. None of the isolates were found to exhibit high-level resistance to vancomycin. However, 3/97 (3.1%) were exhibit resistance to high-level gentamicin based on Kirby-Bauer disk diffusion test. Whereas 48/97 (49.5%) of isolates were observed to be resistant to ampicillin, 28/97 (28.9%) were resistant to penicillin. Surprisingly, among the two strains isolated, 18.6% (n=18/97) of it were resistant to linezolid. Isolates showed resistance to linezolid by disk diffusion test were verified by VITEK-2 automated system (bioMérieux, USA) with MIC ≥8 µg/mL. All antimicrobial susceptibility test and minimal inhibitory concentration (MIC) results were interpreted according to Clinical and Laboratory Standard Institute (CLSI). @*Conclusion, significance and impact of study@#In conclusion, this study has reported the prevalence of linezolid resistant Enterococcus (LRE) in highly intrinsic antibiotic resistant of E. casseliflavus and E. gallinarum in Malaysia poultry farms, alongside with the truancy of vanA strains. The emergence of LRE strains is an alarming problem to the animal husbandry and healthcare setting worldwide. This could lead to potentially untreatable and life-threatening enterococcal infections. Even more worrying is the spread of LRE to geographical regions where these strains were previously unreported, which may pose a global health threat. Antimicrobial surveillance in poultry husbandry is thus, dimly necessary to prevent wide spread of multidrug-resistant bacteria.

Effects of Virus Inactivation Treatment of Plasma Specimen on Plasma Concentration Determination of Vorico- nazole，Linezolid，Vancomycin and Teicoplanin / 中国药房

OBJECTIVE：To study the effects of virus in activation treatment of plasma specimen on plasma concentration determination of voriconzole ，linezolid，vancomycin and teicoplanin. METHODS ：The remaining plasma of 36 inpatients in our hospital after routine blood concentration examination of voriconazole ，linezolid，vancomycin and teicoplanin were collected as specimen（9 drug-contained plasma specimens for each drug ），and merged into three different concentration levels （low，medium， high）of mixed samples according the results of routine blood test. Then the mixed samples with different concentration levels were divided into inactivated group and non-inactivated group ，with 3 samples in each group. The inactivated plasma samples were heated at 56 ℃ for 30 min in metal bath with constant temperature. Non-inactivated group were not treated. After pretreating plasma sample of 2 groups，2-dimensional liquid chromatography was used to detect plasma concentration of the four drugs ；the difference of detection result between inactivated group and non-inactivated group were analyzed. RESULTS ：Plasma samples containing voriconazole，linezolid，vancomycin and teicoplanin were still stable after heating at 56 ℃ for 30 min in metal bath with constant temperature. Compared with non-inactivated group ，relative error of plasma concentration detection result of above 4 drugs were all lower than 15％ in low ，medium，high concentration mixed samples of inactivated group. CONCLUSIONS ：Plasma samples can be inactivated by heating at 56 ℃ for 30 min in metal bath with constant temperature ，when the plasma concentration of voriconazole，linezolid，vancomycin and teicoplanin are determined by 2-dimensional liquid chromatography.

Analysis of Inhibitory Mechanism of Reyanning Mixture Combined with Linezolid Against MRSA and Its Biofilm Based on Metabonomics / 中国实验方剂学杂志

Objective:To investigate the inhibitory effects and mechanism of Reyanning mixture （RYN） combined with linezolid （LNZ） against methicillin-resistant <italic>Staphylococcus aureus</italic> （MRSA） and its biofilm. Method:The minimum inhibitory concentrations （MICs） of RYN and LNZ against MRSA were determined by microdilution assay. The microplate method was used to detect the changes in viable count before and after MRSA administration at four time points （0， 6， 12， 24 h） in the process of biofilm growth. The morphological changes of MRSA after 24 h were observed by scanning electron microscope. Metabonomic technique was applied to analyze the changes in terminal metabolites of endogenous small molecules from MRSA treated by the two drugs at four time points. Result:The MICs of RYN and LNZ were 1/2 of the stock solution concentration and 4 mg·L^-1， respectively. The inhibitory effect of LNZ （2 mg·L^-1） against viable bacteria at 0 h was better than that of 1/16 RYN. At 6， 12， 24 h， 1/16 RYN was superior to LNZ in inhibiting MRSA. The inhibitory effects of RYN combined with LNZ were better than those of RYN or LNZ alone at the four time points. RYN combined with LNZ caused more severe damages to the morphological structure of MRSA biofilm at 24 h than RYN or LNZ alone. Cyclic adenosine monophosphate （cAMP）， adenosine diphosphate （ADP）-<italic>D</italic>-ribose and 2-methylbutanoyl-coenzyme A （2M-CoA）， as the metabolites related to biofilm formation， were immune to LNZ， but 2M-CoA and ADP-<italic>D</italic>-ribose were influenced by RYN at 12 h and 24 h. The combined use of RYN and LNZ interfered with the three metabolites at 24 h. <italic>L</italic>-tryptophan， phenylpyruvic acid， cytidine and sebacic acid were the pharmacometabolic markers of LNZ， and the related biological pathways were phenylalanine， tyrosine and tryptophan biosynthesis and phenylalanine metabolism. Four metabolites such as<italic> L</italic>-histidine， uric acid， and <italic>L</italic>-lysine were the pharmacometabolic markers of RYN， with phenylalanine metabolism and aminoacyl-transfer ribonucleic acid （tRNA） biosynthesis confirmed as the related biological pathways. Nine metabolites such as <italic>L</italic>-tryptophan，<italic> L</italic>-lysine， and sphingosine-1-phosphate were responsible for the efficacy of RYN combined with LNZ. The related biological pathways involved aminoacyl-tRNA biosynthesis， phenylalanine， tyrosine and tryptophan biosynthesis， novobiocin biosynthesis， and tyrosine metabolism. Conclusion:RYN combined with LNZ better exerts the inhibitory effects against MRSA at each time point of its biofilm formation， which is attributed to cAMP metabolism. The synergistic effect resulted from aminoacyl-tRNA biosynthesis and phenylalanine， tyrosine and tryptophan biosynthesis. RYN combined with LNZ can serve as a potentially effective solution to MRSA infection.

Síndrome serotoninérgico como reacción adversa infrecuente ante la sinergia entre Linezolid y Fentanilo: presentación de caso / Serotonin syndrome as an infrequent adverse reaction to synergy between Linezolid and Fentanyl: case presentation

Resumen El síndrome serotoninérgico es una condición potencialmente mortal causada por medicamentos que afectan el metabolismo de la serotonina o que actúan como agonistas directos del receptor de esta o una combinación de ambos. El síndrome da lugar a una variedad de manifestaciones mentales, autonómicas y neuromusculares, que pueden variar desde leves hasta potencialmente mortales. Se reporta el caso clínico de un paciente el cual desarrolló este síndrome por la coadministración y sinergismo de linezolid y fentanilo, con una gran variedad de características clínicas, desde las más sutiles, como cifras tensionales altas de difícil manejo mientras se encontraba bajo el efecto de sedoanalgesia, hasta las manifestaciones más floridas del síndrome posterior a la suspensión de esta. La asociación de estos medicamentos representa una etiología poco informada que puede favorecer la aparición del síndrome, mientras que el uso de benzodiazepinas puede enmascarar el cuadro dificultando su diagnóstico. MÉD.UIS.2020;33(3): 59-66

Abstract Serotonin syndrome is a life-threatening condition caused by medications that affect serotonin metabolism or that act as direct agonists for serotonin receptor or a combination of both. The syndrome gives rise to a variety of mental, autonomic, and neuromuscular manifestations, which can range from mild to life-threatening. We report a clinical case of a patient who developed this syndrome due to the co-administration and synergism of linezolid and fentanyl, with a wide variety of clinical characteristics, from the most subtle, such as high blood pressure levels difficult to manage while under the effect of sedoanalgesia, to the most florid manifestations of the syndrome after 48 hours of its suspension. The association of these drugs represents a poorly reported etiology that may favor the appearance of the syndrome, while the use of benzodiazepines may mask the condition, making its diagnosis difficult. MÉD.UIS.2020;33(3): 59-66

A retrospective cohort study to screen linezolid-induced thrombocytopenia in adult patients hospitalized in the Midwestern Region of Brazil

ABSTRACT Background: Thrombocytopenia (TP) is the major event associated with linezolid (LZD) therapy. We investigated the incidence and risk factors for thrombocytopenia in hospitalized adults who received LZD (1200 mg/day) between 2015 and 2017. HIV-positive, death during follow-up and those with a baseline platelet count ≤100 × 103/mm3 were excluded. Method: TP was defined as a decrease in platelet count of ≥20% from the baseline level at the initiation of linezolid therapy and a final count of <100 × 103/mm3. The odds ratios (OR) for thrombocytopenia were obtained using multivariate stepwise logistic regression analysis. Main results: A total of 66 patients were included (mean age [SD] 62 [18], male gender [%], 37 [56]). LZD-associated TP was identified in 12 patients (18.2%). For TP, the adjusted OR [95% CI] of the platelet count ≤200 × 103/mm3, serum creatinine and renal impairment at baseline were 5.66 [1.15-27.9], 4.57 [1.26-16.5] and 9.41 [1.09-80.54], respectively. Male gender and dosage per weight per day (DPWD) >20 mg/kg/day were not risk factors. Conclusion: The results showed that the incidence of linezolid-induced thrombocytopenia was lower in patients with normal renal function and higher in those with platelet counts ≤200 × 103/mm3 or serum creatinine >1.5 mg/dL at the start of the treatment.